Psoriasis is a common chronic and recurrent disease characterized by hyperproliferation of the basal layer of the epidermis resulting in dry, well-circumscribed, silvery-scaled maculopapules and plaques of various sizes. The lesions occur predominently on the elbows, knees, scalp, and trunk and microscopically show characteristic parakeratosis and elongation of rete ridges. General health is rarely affected, although psoriatic arthritis, a destructive form of arthritis in the fingers and toes which often closely resembles rheumatoid arthritis, may develop in some patients.
Onset of psoriasis is usually gradual, however factors precipitating psoriatic eruptions include local trauma and occasionally severe sunburn, irritation, topical medications, chloroquine antimalarial therapy and withdrawal of systemic corticosteroids.
Although the cause of psoriasis is unknown, the following evidence implies that abnormalities in the cellular immune function exist:
1. depressed reactivity to contact allergen; PA1 2. decreased delayed reactivity to interdermal challenge with antigen; PA1 3. depressed response to major histocompatibility antigens; PA1 4. depressed response to mitogens; PA1 5. depressed lymphokine production to antigen challenge; PA1 6. normal and decreased numbers of T-lymphocytes; and PA1 7. decreased to normal suppressor T-lymphocyte function.
No current therapeutic methods exist which assure a cure for psoriasis. The simplest forms of treatment include topical applications of lubricants, keratolytics, and topical corticosteroids. Furthermore, a new treatment utilizing psoralens and high intensity ultraviolet A (PUVA) involves the oral administration of methoxsalen (average dose 40 mg) followed by exposure of the skin to long-wave ultraviolet light (330 to 360 nm). Although this treatment may produce remissions for several months, repeated treatments with intensive light may cause skin cancer. Finally the most effective treatment in severe disabling psoriasis that is unresponsive to topical agents or PUVA involves oral administration of methotrexate.
Interleukin-2 (IL-2) is a lymphokine, produced predominantly by helper T-cells, which modulates the activation and proliferation of cytotoxic T-cells, natural killer (NK) cells, B cells, lymphokine-activated killer (LAK) cells, and possibly T suppressor cells. Human IL-2 has been purified and its molecular structure has been determined. It is composed of a single polypeptide chain of 133 amino acid residues with a molecular weight of approximately 15,000 daltons which may be variably glycosylated without loss of biological activity. IL-2 and analogs thereof have been produced using recombinant DNA technology. For example, recombinant methionyl human interleukin-2 alanine-125 [r-met Hu IL-2 (ala-125)] is a non-glycosylated analog of natural human IL-2 which retains the full biological activity of recombinant natural sequence human IL-2 and is stable in vitro for at least six months. R-met Hu IL-2 (ala-125) differs from naturally-occurring human IL-2 by having an additional methionyl residue at position 1 and having the cysteine at position 125 substituted with an alanine residue. Its amino acid sequence, as well as methods for its production and purification, are disclosed in European patent publication number 136,489.
In clinical studies of recombinant IL-2 performed to date, toxicity has been dose related and has consisted mainly of fever, chills, rigors, malaise, diarrhea, fluid retention, nausea, vomiting, and arthralgias. Additionally, increased serum creatinine and transaminases, anemia, eosinophilia, leukocytosis, rash, stomatitis, hypotension, joint pain, and mental confusion have been reported.
Gaspari, et al., JAMA, 258: 1624-1629 (1987) reported the cutaneous effects which occurred in ten patients undergoing immunotherapy with IL-2 and autologous lymphokine-activated killer (LAK) cells, i.e., a subset of lymphoid cells activated with IL-2 which can mediate the regression of pulmonary and hepatic metastases originating from a variety of tumor cell lines, to treat cancer. Among their observations, Gaspari, et al. reported that pharmacologic doses of IL-2 exacerbated erythrodermic flare of psoriasis in two patients who presented with psoriasis.
One object of the present invention is to provide therapeutic methods of treating a subject for psoriasis.